François Carreaux

Selectivity, Cocrystal Structures, and Neuroprotective Properties of Leucettines, a Family of Protein Kinase Inhibitors Derived from the Marine Sponge Alkaloid Leucettamine B

DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimers disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimers disease.

Boronic ester as a linker system for solid phase synthesis

Abstract A method for attaching boronic acids to a macroporous polymer-supported 1,3-diol was developed. Chemical modifications of some polymer-bound arylboronic acids were realised using various reaction conditions. Trans-esterification gave new boronates in high purity while oxidative cleavage directly led to phenols.

Ruthenium-Catalyzed Synthesis of Allylic Alcohols : Boronic Acid as a Hydroxide Source

Secondary allylic alcohols were synthesized from linear allylic halides or carbonates using a catalytic amount of a ruthenium complex in the presence of boronic acid. The effects of solvent, base, ruthenium precursor, and boronic acid were fully explored, and the scope of the reaction was extended to various substrates. We also describe a preliminary investigation towards an enantioselective process.

Synthesis of functionalized γ-and δ-lactones via polymer-bound epoxides

Abstract Solid phase synthesis of epoxides from alkenoic acids followed by ring-opening reactions with sodium azide or thiophenols and subsequent cleavage from the polymeric support afford γ-and δ-lactones in good yields and high purity.

Synthesis of alkenyl boronates from allyl-substituted aromatics using an olefin cross-metathesis protocol.

An efficient synthesis of 3-aryl-1-propenyl boronates from pinacol vinyl boronic ester and allyl-substituted aromatics by cross metathesis is reported. Although the allylbenzene derivatives are prone to isomerization reaction under metathesis conditions, we found that some ruthenium catalysts are effective for this methodology. This strategy thus provides an interesting alternative approach to alkyne hydroboration, leading to the preparation of unknown compounds. Moreover, the boron substituent can be replaced by various functional groups in good yields.

Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors.

New derivatives of the marine alkaloid leucettamine B were prepared in five steps with overall yields ranging from 23 to 30%. The key step of our strategy has been the sulfur/nitrogen displacement under solvent-free microwave irradiation of (5Z) 5-benzo[1,3]-dioxo-5-ylmethylene-2-ethylsulfanyl-3,5-dihydroimidazol-4-one 3 with a mono-protected ethylenediamine 2. After deprotection of the N-Boc group, the amino derivative of leucettamine B 5 was subjected to reductive amination in two steps with retention of configuration of the double bond, to lead to eight new analogs of leucettamine B. The effect of these compounds on CK1alpha/beta, CDK5/p25, and GSK-3alpha/beta were investigated.

Microwave-mediated solventless synthesis of new derivatives of marine alkaloid Leucettamine B

New access to N-alkyl derivatives of the marine alkaloid Leucettamine B are described using two three-step convergent routes. For the formation of the 2-amino imidazolone ring, the key steps involve solvent-free condensations under microwaves and guanylation reactions with non-sterically hindered primary amines.

Synthesis of highly functionalized homochiral azetidines and azetidine-2-carboxylic esters

Abstract Homochiral (2S, 3S)-3-benzyloxy-2-formyl-azetidines 2, (2S, 3S)-3-benzyloxy-2-carbomethoxy-azetidines 3 and the highly strained (2S)-N-p-methoxyphenyl-2-silyloxymethyl-3-azetidinone 4 were successfully synthesized starting from diethyl-L-tartrate. The suitably functionalized azetidine ring is formed in a single synthetic operation with minimum protecting group chemistry.

[3,3]-Sigmatropic rearrangement of boronated allylcyanates: a new route to α-aminoboronate derivatives and trisubstituted tetrahydrofurans.

[3,3]-Sigmatropic cyanate-isocyanate rearrangement provides a powerful tool for the preparation of α-isocyanato allylboronic esters, which can be further trapped with a variety of nucleophiles. Hydrogenation gave the corresponding α-aminoboronates derivatives while addition of aldehydes afforded homoallylic alcohols, (tetrahydrofuran-2-yl)carbamate, ether, or urea derivatives.

(Z)-1,4-Diamino-2-butene as a vector of boron, fluorine, or iodine for cancer therapy and imaging: Synthesis and biological evaluation

Polyamine vectors are attractive for tumor targeting. We envisaged (Z)-1,4-diamino-2-butene (Z-DAB), an unsaturated analogue of putrescine as vector of (10)B, (18)F and (131)I for boron neutron capture therapy (BNCT), and tumor imaging by positron emission tomography or scintigraphy respectively. In the present work, the synthesis and characterization of new derivatives of Z-DAB were reported. Z-DAB was actively transported in cells via the polyamine transport system and converted into the spermidine analogue.(E)-2-iodo-1,4-diamino-2-butene (E-I-DAB) was not taken up by the polyamine transport system and may not be suitable for tumor imaging. In contrast, (Z)-2-[4-(5,5-dimethyl-dioxaborinan-2-yl)phenyl]methyl-1,4-diamino-2-butene (Z-4-Bbz-DAB) was a substrate of the transport system and allowed significant boron accumulation in 3LL cells. Its potential in BNCT will be evaluated.